4-Anilidopiperidine analgesics developed by Janssen Pharmaceuticals are a class of clinically important synthetic opiates. These include Carfentanil, Sufentanil, Alfentanil, and Remifentanil.

The syntheses of these compounds have been disclosed in the patent and open literature. A partial general synthetic scheme is shown below.

With R1═PhCH2, commercially available 1-benzyl-4-piperidinone is subjected to a Strecker reaction with aniline to form an amino nitrile. The conversion of the nitrile group to the methyl ester occurs as follows. The nitrile is converted to an amide under strongly acidic conditions. The amide is then converted to a carboxylic acid under strongly basic conditions. The resulting acid is then converted to the intermediate anilino methyl ester either via carboxylic acid or its sodium salt. The intermediate anilino methyl ester can be transformed, after numerous divergent steps, into Carfentanil, Sufentanil, Alfentanil, or Remifentanil.
With R2═PhCH2CH2, the yield of the hydrolysis of the nitrile under high acidic conditions, e.g. sulfuric acid, to the corresponding amide is very low (about 14% or less). Non-acidic conditions also yield less than satisfactory results.
In U.S. Pat. No. 5,106,983 (Reiff, et al.), 4-anilidopiperidine analgesics as above described are produced by the series of reactions as noted above including a Strecker synthesis to give an aminonitrile and the nitrile is then converted to a formamide with formic acid and acetic anhydride. This compound is hydrolyzed to an imidate with refluxing methanolic hydrogen chloride. Decomposition of this in dilute base gives an amide. The net yield for these three steps which substitutes for the acid hydrolysis of the nitrile is about 47%. This three step procedure to replace the sulfuric acid hydrolysis is tedious.